The long-term objective of our research is to elucidate how arsenic (As) affects xenobiotic bioavailability anc increases the incidence of atherosclerotic disease, diabetes mellitus as well as several types of drug resistanl cancers. In this application, studies will focus on elucidating the effects of environmentally relevant levels oi As on the expression and function of two ABC (ATP Binding Cassette) transporters: the cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance protein 2 (MRP2). CFTR is a C channel that plays an important role in salt homeostasis. MRP2 transports xenobiotics, including chemotherapeutic drugs, toxins, and arsenicrglutathione conjugates out of cells and, thereby, plays a role in xenobiotic excretion in bile and urine, protects the brain from xenobiotic and toxic compounds and limits th< intestinal absorption of drugs. The proposed studies are designed to test the hypothesis that arsenic modulates hormonal regulation of ABC transporter gene expression and function. Specifically, the hypothesis is that As is an endocrine disrupter that blocks cortisol-glucorticoid receptor activation of CFTR gene expression and, thereby, interferes with salt homeostasis, and that As regulates xenobiotic excretion anc bioavailability by regulating MRP2 gene expression in kidney, intestine and the blood brain barrier. To test the hypothesis three specific aims are proposed. Specific Aim #1 will test the hypothesis that As perturbs NaC homeostasis by inhibiting CFTR gene expression and function. Specific Aim #2 will test the hypothesis tha As modulates MRP2 gene expression and function, and thereby affects xenobiotic excretion am bioavailability. Specific Aim #3 will test the hypothesis that As modulates the expression of novel genes tha regulate MRP2 and CFTR. To these ends a combination of biochemical, molecular, and live cell imaging approaches will be employed to study the effects of As on CFTR and MRP2 gene expression and function in kidney, intestine, operculum and blood brain barrier. The proposed studies will be highly interactive with Projects 2, 4 and 5, and will utilize all of the Cores. These studies will enhance our understanding of the cellular mechanisms whereby As regulates ATP transporter gene expression and function.